NUTRIGENOMICS, THE NEW FRONTIER IN NUTRITION RESEARCH

Giuditta Perozzi , Chiara Murgia and Carlo Cannella #

INRAN - National Research Institute on Food & Nutrition, Roma, Italy

# University of Rome La Sapienza, Roma, Italy

Parma, october 4, 2007

NUTRIGENOMICS, THE NEW FRONTIER IN NUTRIGENOMICS, THE NEW FRONTIER IN NUTRITION RESEARCHNUTRITION RESEARCH

Giuditta Perozzi , Chiara Murgia and Carlo Cannella #

INRAN - National Research Institute on Food & Nutrition, Roma, Italy

# University of Rome La Sapienza, Roma, Italy

Parma, Parma, october october 4, 20074, 2007

SIMULTANEOUS CHANGES IN SEVERAL PATHWAYS DEFINE ARESPONSE PHENOTYPE

MOLECULAR NUTRITION STUDIES

DIETDIET

NUTRIENTS AND BIOACTIVE FOOD

COMPONENTS

NUTRIENTS AND BIOACTIVE FOOD

COMPONENTS

MetabolismMetabolism

GENEEXPRESSION

GENEEXPRESSION

HOMEOSTASISHOMEOSTASIS

Signal transductionSignal transduction

TRANSCRIPTION FACTORS MEDIATING NUTRIENT-GENE INTERACTIONS

MOLECULE TRANSCRIPTION FACTORS

MACRONUTRIENTSLipids Fatty acids PPARs, SREBPs, LXR, HNF4, ChREBP

Cholesterol SREBPs, LXRs, FXRCarbohydrates Glucose USFs, SREBPs, ChREBP

Proteins Aminoacids C/EBPs

MICRONUTRIENTSVitamins Vitamin A RAR, RXR

Vitamin D VDRVitamin E PXR

Minerals Calcium Calcineurine/NF-ATsIron IRP1, IRP2Zinc MTF1

BIOACTIVE MOLECULESFlavonoids ER, NF-kB, AP1Xenobiotics CAR, PXR

Regular uptake Regular uptake of of specific specific food components food components was was associated withassociated with decreased incidence ofdecreased incidence of chronic chronic diseases diseases such assuch as cardiovascular cardiovascular diseases diseases and and some types of some types of diabetes diabetes and and cancercancer..

These results have These results have led to the concept ofled to the concept ofOPTIMAL NUTRITIONOPTIMAL NUTRITION,, which which includes includes not not onlyonly adequate nutrient uptake to meet adequate nutrient uptake to meet physiological needs, physiological needs, but alsobut also the the presence presence of of food componentsfood components shown shown to be capableto be capable of of dicreasing dicreasing the risk of the risk of chronic diseases chronic diseases

FOOD COMPONENTS AS HEALTH FACTORS

The majority of The majority of nutritionally related chronic diseases nutritionally related chronic diseases arearePOLYGENIC AND POLYGENIC AND MULTIFACTORIALMULTIFACTORIAL,, as their onset as their onset and and progression progression are are affected by affected by multiple multiple genes genes (and GENE (and GENE VARIANTS)VARIANTS) as well as by as well as by SEVERAL ENVIRONMENTAL SEVERAL ENVIRONMENTAL FACTORSFACTORS

Ghazalpour et Ghazalpour et al., 2004al., 2004

Individual Individual genetic makeupgenetic makeup

Environmental stimuliDiseaseDisease

riskrisk

GENEGENE--NUTRIENT INTERACTIONNUTRIENT INTERACTIONAND DISEASE RISKAND DISEASE RISK

HealthyUnhealthyFood habits

Low risk High risk

Low riskHigh risk

Environmental Environmental factors factors (FOOD)(FOOD)

INDIVIDUALS CONSUMING THE SAME INDIVIDUALS CONSUMING THE SAME DIETDIET HAVE DIFFERENT DISEASE RISK HAVE DIFFERENT DISEASE RISK DEPENDING ON THEIR DEPENDING ON THEIR GENETIC MAKEUPGENETIC MAKEUP

INDIVIDUALS CARRYING THE SAMEINDIVIDUALS CARRYING THE SAMEGENOTYPE GENOTYPE HAVE DIFFERENT DISEASE HAVE DIFFERENT DISEASE RISK DEPENDING ON THEIRRISK DEPENDING ON THEIR DIETARY DIETARY HABITSHABITS

Park et al., 1997. J. Nutr. 127: 566

GENETIC MAKEUP AFFECTS PHYSIOLOGICAL RESPONSE TO DIET

PROTECTIVE ALLELESPROTECTIVE ALLELESvsvs

““RISKYRISKY”” ALLELESALLELES

NUTRIGENOMICS

Study Study of of nutrientnutrient--gene interactions gene interactions at the at the genome genome level level ((transcriptometranscriptome, , proteomeproteome, , metabolomemetabolome) ) with with

the the aim aim of of lowering lowering the the risk risk of of dietdiet--related related diseasesdiseases

But also…..

Study Study of the of the individual genetic individual genetic makeup makeup ((genotypegenotype) and ) and its effect its effect on on nutrient nutrient

metabolism metabolism (NUTRIGENETICS)(NUTRIGENETICS)

HyppocratesHyppocrates::Leave Leave medicines in the chemistmedicines in the chemist’’s pot if s pot if you can cure your you can cure your patients patients with foodwith food

THE LONGTHE LONG--TERM GOAL OF TERM GOAL OF NUTRIGENOMICS IS TO IDENTIFY NUTRIGENOMICS IS TO IDENTIFY

NUTRITIONNUTRITION--RELATED DISEASE RELATED DISEASE GENES AND TO DEVELOP GENES AND TO DEVELOP

PERSONALIZED DIETS BASED ON PERSONALIZED DIETS BASED ON GENETIC MAKEUP TO LOWER GENETIC MAKEUP TO LOWER

DISEASE RISKDISEASE RISK

Some Some dietary compounds affect dietary compounds affect gene gene expressionexpression

Some Some dietdiet--regulated genes could regulated genes could play a play a role role in the in the onsetonset, , progressionprogression, and/or , and/or severity severity of of chronic chronic diseasesdiseases..

Diet Diet can can therefore represent therefore represent a a risk factor for risk factor for some some chronic diseaseschronic diseases

Influence Influence of of diet diet on on health depends health depends on on individual individual genetic genetic makeup.makeup.

““PERSONALIZED DIETSPERSONALIZED DIETS”” BASED ON BASED ON NUTRITIONAL REQUIREMENTS, NUTRITIONAL NUTRITIONAL REQUIREMENTS, NUTRITIONAL

STATUS, AND GENOTYPE COULDSTATUS, AND GENOTYPE COULD PREVENT, PREVENT, MITIGATE OR CURE CHRONICMITIGATE OR CURE CHRONIC DISEASEDISEASE

NUTRIGENOMICS CONCEPTS

COMPLETION OF HUMAN COMPLETION OF HUMAN GENOME SEQUENCING IN 2001 GENOME SEQUENCING IN 2001

((International Human Genome International Human Genome Sequencing ConsortiumSequencing Consortium))

BIOINFORMATICSBIOINFORMATICS ((acquisitionacquisition, management, , management,

storagestorage, , retrieval retrieval of high of high throughput datasetsthroughput datasets))

BIOCOMPUTATIONBIOCOMPUTATION ((analysis analysis of high of high throughput throughput

datasetsdatasets))

HIGH THROUGHPUT NUTRIGENOMICS TECHNOLOGY

Identification Identification of of genetic genetic polymorphisms associated with polymorphisms associated with

increased disease risk increased disease risk and of and of their their modulation with dietary interventionmodulation with dietary intervention

NUTRIGENETICS

SNP = Single SNP = Single Nucleotide Polymorphism Nucleotide Polymorphism

Allelic Allelic gene gene variant variant detected within detected within a a population group with population group with higher frequency higher frequency than expected from than expected from independent independent mutationsmutations

APR 1999 - OTT 2005 SNP CONSORTIUM (20 labs in 6 nations)

ANALYSIS OF > 1 million SNPs

APR 1999 APR 1999 -- OTT 2005OTT 2005 SNP CONSORTIUM (20 labs in 6 nations)

ANALYSIS OF >ANALYSIS OF > 1 1 million SNPsmillion SNPs

•• THE GENOMES OF UNRELATED HUMAN THE GENOMES OF UNRELATED HUMAN BEINGSBEINGS IS 99.9% IDENTICALIS 99.9% IDENTICAL

•• INDIVIDUAL GENETIC VARIATION IS INDIVIDUAL GENETIC VARIATION IS ACCOUNTED FOR BY THE REMAINING 0.1% ACCOUNTED FOR BY THE REMAINING 0.1% INDIVIDUAL VARIATIONINDIVIDUAL VARIATION

Small changes in gene sequence can cause significant, demonstrated and unequivocal changes in enzyme activity or protein function.

Such changes can have significant health effects.

Ghazalpour et Ghazalpour et al., 2004al., 2004

Dietary and/or Dietary and/or lifestyle changes can lifestyle changes can

have a positive have a positive effect and overcome effect and overcome

the effect of the the effect of the gene variantgene variant

LIPID TRANSPORTLIPID TRANSPORT

–– Cholesteryl ester Cholesteryl ester transport protein transport protein CETPCETP

–– Phospholipid transport Phospholipid transport protein protein PLTPPLTP

–– Microsomal tryglyceride Microsomal tryglyceride transport transport protein protein MTPMTP

–– Fatty Fatty Acid Acid transport transport protein protein FATP1FATP1

–– Apolipoprotein Apolipoprotein EE–– Apolipoprotein Apolipoprotein AA

BLOOD PRESSUREBLOOD PRESSURE

–– eNOSeNOS–– EndothelinEndothelin--11–– Prostacyclin Prostacyclin

synthasesynthase

EXAMPLES: 1. SNPs ASSOCIATED WITH DIFFERENTIAL CVD RISK

Effect Effect of APOA1 (SNP of APOA1 (SNP --75G/A) on 75G/A) on serum serum concentration concentration of of HDLHDL--cholesterolcholesterol, in , in response response

to diets containing different amounts to diets containing different amounts of of PUFAsPUFAs

HDL-

C (m

mol/L

)

EXAMPLES - 2. LACTOSE INTOLERANCE70% 70% AfroAfro--Americans Americans 90% 90% Asian AmericansAsian Americans53% 53% Mexican Americans Mexican Americans 74% American 74% American Indians Indians

Study Study of 9 of 9 finnish finnish families identified families identified 2 2 SNPs SNPs in thein thepromoterpromoter region region of of the LACTASEthe LACTASEGENE GENE responsible responsible for lactose for lactose TOLERANCETOLERANCE

GENOTYPING OF LACTOSE INTOLERANCE

Methionine biosynthesis is folate dependent

and controls homocysteine levels

EXAMPLES - FOLIC ACID SUPPLEMENTATION

THE PRESENCE OF THE C677T ALLELE OF THE MTHFR GENE LEADS TO INCREASED SERUM LEVELS OF HOMOCYSTEINE WHEN DIET LACKS ADEQATE

AMOUNTS OF FOLATE

FOLATE SUPPLEMENTATION CAN COUNTERACT FOLATE SUPPLEMENTATION CAN COUNTERACT ADVERSE GENOTYPE AND DECREASE RISK OF CVDADVERSE GENOTYPE AND DECREASE RISK OF CVD

MULTIDISCIPLINARITY OF NUTRIGENOMICS RESEARCH

Diet = Nutritional ScienceGene expression = Molecular BiologyIndividual = Genetics/GenomicsHealth = Physiology

……a a science investiganting science investiganting SYSTEMS BIOLOGY SYSTEMS BIOLOGY is is necessarily necessarily MULTIDISCIPLINARYMULTIDISCIPLINARY

INTERNATIONAL NETWORKS

Primary aims Primary aims of of NuGONuGO::

•• Train European scientists to use postTrain European scientists to use post--genomic genomic technologies technologies in in nutrition researchnutrition research•• Develop Develop and integrate and integrate genomic technologies for genomic technologies for the the benefit of benefit of European nutritional scienceEuropean nutritional science•• Facilitate the Facilitate the application application of of these technologies these technologies in in nutritional research worldnutritional research world--widewide•• Create the Create the worldworld--leading virtual centre leading virtual centre of of excellence excellence in in nutrigenomicsnutrigenomics

NuGO is NuGO is a a EuropeanEuropean--funded funded Network of Network of ExcellenceExcellence, , linking genomicslinking genomics, , nutrition nutrition and and health researchealth researcNuGO is funded by NuGO is funded by EC EC -- VI FP VI FP -- Food Food Quality Quality and and Safety Priority Safety Priority (2004(2004--2009)2009)

NUTRIGENOMICS @ INRAN

Identification Identification of candidate of candidate genes genes and and proteins proteins involved involved in in nutrient modulation nutrient modulation of of cardiovascular cardiovascular diseases diseases and and Type Type 2 2 Diabetes Diabetes (TRANSCRIPTOMICS, (TRANSCRIPTOMICS, PROTEOMICS)PROTEOMICS)

Identification Identification of candidate of candidate genes genes and and proteins proteins modulating bioavailability modulating bioavailability of of bioactive bioactive food food components components ((TRANSCRIPTOMICS, PROTEOMICSTRANSCRIPTOMICS, PROTEOMICS))

Modulation Modulation of of metabolic disease risk by postmetabolic disease risk by post--prandial prandial phenomena phenomena in relation in relation to meal to meal pattern pattern (METABOLOMICS)(METABOLOMICS)

Identification Identification of of genotypes associated with genotypes associated with differential disease risk differential disease risk in in response to diet response to diet (BIOCOMPUTATION)(BIOCOMPUTATION)

Jim Kaput, 2005Jim KaputJim Kaput, 2005, 2005

Eat well Exercise

Chooseancestors

wisely

The 2007 path The 2007 path to personalized nutritionto personalized nutrition…………